Background: The management of Post-Acute COVID-19 Sequelae (PASC), especially pulmonary sequelae, still remains a challenge. MicroRNAs (miRNAs) have a potential use as biomarkers and could provide information on pathobiological mechanisms.

Aim: First, to analyze the potential of miRNAs quantified during ICU stay as biomarkers of respiratory sequelae. Second, to decipher the molecular mechanisms associated with the sequelae.

Methods: Multicenter study including 491 critically ill patients from 19 Spanish ICUs. Diffusing capacity (DLCO) <80% defined lung diffusion impairment after hospital discharge (2-12 months). Plasma samples were collected within the first 48 hours upon ICU admission. A 16-miRNA panel was analyzed by RT-qPCR.  The integration of miRNA levels with a clinical model previous published by our group was performed using stepwise logistic regression.

Results: The follow-up was completed in 90 patients (median age 62 years, 22.2% females). The multivariable analysis selected three miRNAs: miR-16-5p, miR-148a-3p and miR-323a-3p which significantly improve the discrimination (AUC from 0.78 to 0.89) and the classification of the survivors (IDI of 0.208 and NRI of 0.876) of the clinical model. The enrichment analysis identified potential mechanistic pathways implicated in respiratory sequelae.

Conclusions: A blood-based miRNA signature improves early prediction of respiratory sequelae in survivors of critical COVID-19. The biological role of miRNA profile provides molecular information about the mechanisms associated to the PASC.

Funding: ISCIII (PI20/00577, COV20/00110, CP20/00041, FI21/00187), UNESPA.